Tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are two antiretroviral medications used for the treatment and prevention of HIV/AIDS. This study will examine how these medications are processed in the body of people who are HIV-infected, as well as in people who are HIV-uninfected.

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:

Comparison of the first dose tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) area under the concentration-time curve (AUC) in HIV-uninfected adults versus HIV-infected adults [ Time Frame: Measured at the time of the first dose ] [ Designated as safety issue: No ]

Comparison of average steady-state plasma deoxyguanosine concentrations before therapy and after 30 days of TDF/FTC therapy [ Time Frame: Measured through Day 30 ] [ Designated as safety issue: No ]

Comparison of TFV-DP and FTC-TP in HIV-seroconverters versus matched non-seroconverters from the iPrEx study [ Time Frame: Measured throughout the 4-year study ] [ Designated as safety issue: No ]

Modeling describing intracellular pharmacokinetics of TFV-DP and FTC-TP in PBMCs so dosing strategies can be tested on the model to identify the optimal dosing that most rapidly achieves and sustains the desired prophylactic threshold for HIV prevention [ Time Frame: Measured throughout the 4-year study ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Definition of the terminal elimination phase of TFV-DP and FTC-TP in HIV-uninfected adults [ Time Frame: Measured from Day 30 to 60 ] [ Designated as safety issue: No ]

Evaluation of markers of cell activation (HLA-DR and CD38 expression) and the relationship to TFV-DP and FTC-TP concentrations [ Time Frame: Measured through Day 30 ] [ Designated as safety issue: No ]

Effects of TFV-DP and FTC-TP (and plasma EFV) on plasma HIV-RNA and CD4 counts in the HIV-infected participants [ Time Frame: Measured through Day 60 ] [ Designated as safety issue: No ]

Evaluation of relationships between adherence measures collected in iPrEx with TFV-DP and FTC-TP [ Time Frame: Measured throughout the 4-year study ] [ Designated as safety issue: No ]

Comparison of TFV-DP and FTC-TP between African-American and non-African-American participants [ Time Frame: Measured through Day 30 ] [ Designated as safety issue: No ]

Evaluation of polymorphisms in MRP2 (eg, -24C>T, 1249G>A), MRP4 (eg, 1612C>T, 3463G>A, 3724G>A, 4131T>G), BCRP (eg, 421C>A, 34G>A) and other potentially important enzymes for the study drugs for relationships with pharmacokinetics and pharmacodynamics [ Time Frame: Measured throughout the 4-year study ] [ Designated as safety issue: No ]

Comparison of Day 30 AUC and overall AUC (AUC over Day 1 to Day 30) TFV-DP and FTC-TP in HIV-uninfected versus HIV-infected participants [ Time Frame: Measured through Day 30 ] [ Designated as safety issue: No ]

HLA-DR / CD38 on T cells will be correlated with changed intracellular and extracellular purine levels in the HIV-uninfected participants to address potential immune-modulation associated with PNP inhibition [ Time Frame: Measured throughout the 4-year study ] [ Designated as safety issue: No ]

Characterization of the ratios of TFV-DP and FTC-TP to corresponding endogenous deoxyribose nucleotides [ Time Frame: Measured throughout the 4-year study ] [ Designated as safety issue: No ]

Comparison of TFV-DP and FTC-TP according to iPrEx study sites [ Time Frame: Measured throughout the 4-year study ] [ Designated as safety issue: No ]

HIV-infected participants will receive FTC, TDF, and EFV for 60 days by prescription from their physicians. Participants will receive Truvada (FTC/TDF) and EFV for the first 30 days. After Day 30, participants may switch to the TDF/FTC/EFV co-formulation through Day 60 as directed by their physician.

Tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are both nucleoside reverse transcriptase inhibitors (NRTIs), a class of medications used for the treatment and prevention of HIV/AIDS. Analyzing how the body interacts with these medications at the cellular level may lead to more effective dosing strategies for both HIV prevention and treatment. This study will examine the pharmacokinetics of TDF and FTC at the cellular level in HIV-infected people (N=20) and HIV-uninfected people (N=20). HIV-infected participants will be allowed to take part in this study only if their doctor already plans to prescribe TDF, FTC, and efavirenz (EFV) for their HIV care, regardless of their participation in this study. HIV-infected participants will receive Truvada (TDF/FTC) and EFV for the first 30 days. After Day 30, participants will continue to receive TDF, FTC, and EFV through Day 60, under the direction of their physician. HIV-infected participants will remain on their therapy throughout the study as part of their HIV care. HIV-uninfected volunteers will receive 30 days of Truvada (TDF/FTC).

The study duration is 60 days. Study visits will occur at baseline and on Days 1, 3, 7, 20, 30, and 60. At most study visits, participants will undergo blood and urine collection for pharmacology studies, a medication history review, and an adverse effects questionnaire. HIV-uninfected participants will also attend two additional study visits at Days 35 and 45 - while off study medication - for blood and urine collection, adverse effects questionnaires, and a medication history review. At varying study visits during the first 30 days, all participants will undergo one rectal biopsy, female participants will undergo one cervical cell and fluid sampling procedure, and male participants will provide one semen sample. In addition to the collections from enrolled participants, study researchers will also analyze previously collected and stored blood samples from participants in the "Chemoprophylaxis for HIV Prevention in Men (iPrEx)" study, which examined the use of TDF and FTC for the prevention of HIV in men who have sex with men (MSM).

Eligibility

Ages Eligible for Study:

18 Years to 55 Years (Adult)

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

Yes

Criteria

Inclusion Criteria for HIV-Uninfected Participants:

Ability to provide informed consent

Ability to comply with the study procedures

Exclusion Criteria for HIV-Uninfected Participants:

Positive screening test for HIV infection

Positive screening test for hepatitis B (HBV) infection

Pregnant or planning to become pregnant in the 3 months after study entry

Breastfeeding

If sexually active and fertile (no tubal ligation or hysterectomy), refusal to use two forms of birth control (e.g., condom and hormonal birth control) during the 60-day study

Estimated glomerular filtration rate (GFR) less than 60 mL/min/1.73 m^2 by the Modification of Diet in Renal Disease (MDRD) method

Any grade I or higher abnormality in hemoglobin, platelets, serum phosphorous, and lipase on the screening visit; grade I abnormalities in other labs will be evaluated on a case by case basis (using DAIDS criteria)

Any concomitant medication (or herbal product) that, in the opinion of the investigators, would interfere with the study outcomes (acceptable medications include acetaminophen, occasional ibuprofen/NSAID, vitamins, and birth control pills)

History of pathologic bone fractures

Any chronic or acute medical condition that, in the opinion of the investigator, would interfere with study conditions, such as cancer, heart disease, or diabetes

Body weight under 110 pounds

Inclusion Criteria for HIV-Infected Participants:

HIV-infected adults (HIV documented in medical record or by the primary clinician)

Clinician/participant plan to initiate TDF/FTC/EFV therapy and agree to separate TDF/FTC and EFV prescriptions for the initial 30 days of the study

Ability to provide informed consent

Ability to comply with the study procedures

Exclusion Criteria for HIV-Infected Participants:

Antiretroviral therapy in the preceding 6 months

Pregnant or planning to become pregnant in the 3 months after study entry

Breastfeeding

If sexually active and fertile (no tubal ligation or hysterectomy), refusal to use two forms of birth control (e.g., condom and hormonal birth control) during the 60-day study

Greater than a grade II abnormality in hemoglobin or platelets. Greater than a grade II abnormality in other clinical chemistry or hematology tests that, in the opinion of the investigators (principal investigator, study coordinator, and study physician) and primary clinician, would preclude participation in the study. DAIDS grading criteria will be used.

Use of any investigational medication in the 30 days before study entry

Daily anticoagulant therapy (daily aspirin or NSAIDs will be allowed if discontinued for 1 week prior to the rectal biopsy)

Any concomitant medication (or herbal product) that, in the opinion of the investigators, would interfere with the study outcomes (acceptable medications include acetaminophen, occasional ibuprofen/NSAID, vitamins, and birth control pills)

Any chronic or acute medical condition that, in the opinion of the investigator, could lead to emergent health complications, or could interfere with the participant's ability to follow study procedures

Body weight under 110 pounds

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01040091